JP2007511482A5 - - Google Patents

Description

A branched polyester (Glu-PLG) having a central glucose moiety with a radial linear polylactide-co-glycolide chain is preferably about 10,000 to 200,000, preferably 25,000 to 100,000, especially It has a weight average molecular weight _Mw of 35,000 to 60,000, for example about 50,000 Da, and has a polydispersity of, for example, 1.7 to 3.0, for example 2.0 to 2.5. Intrinsic viscosities of star polymers with M _w 35,000 or M _w 60,000 are 0.36 or 0.51 dl / g in chloroform, respectively. A star polymer with M _w 52,000 has a viscosity of 0.475 dl / g in chloroform.

b) Sodium carboxymethylcellulose (CMC-Na), preferably having a low molecular weight. The viscosity can be, for example, up to 20 cP with a 2% aqueous solution, or a viscosity of 8 to 25 mPa s. Conveniently, the degree of substitution is from about 0.5 to about 1.45, Ru preferably about 0.7 Der. Typically the sodium content is about 5% to about 12%.
Preferably, the CMC-Na is present in an amount from about 0.1 to about 20%, such as about 5% by weight of the microparticles.

d) Polyethylene glycol having a weight average molecular weight of, for example, about 1,000 to about 10,000 Da, preferably about 1,000 to about 3,350 Da. Suitable examples include those generally known and commercially available from Dow & Union Carbide under the trade name Carbowax®, for example, Mw of 3,350 Da. Polyethylene glycol with a weight average molecular weight of 3,350 Da has a viscosity of 76 to 110 cSt at 98.9 ± 0.3 ° C. 1000 to 3500 DA of Mw polyethylene glycol has a viscosity of 16 to 123 cSt at 98.9 ± 0.3 ° C.

A suitable example of the stabilizer of step (iib) is a) polyvinyl alcohol (PVA) preferably having a weight average molecular weight of about 10,000 to about 150,000 Da, such as about 30,000 Da. Conveniently, the polyvinyl alcohol has a low viscosity with a dynamic viscosity of about 3 to about 9 mPa s when measured in a 4% aqueous solution at 20 ° C. or with DIN 53015. Suitably, the polyvinyl alcohol is obtained by hydrolysis of polyvinyl acetate. Preferably, the polyvinyl acetate content is from about 10 to about 90% of the polyvinyl alcohol. Conveniently, the degree of hydrolysis is about 85 to about 89%. Typically, the remaining acetyl content is about 10 to 12%. Preferred trademarks include Mowiol® 4-88, 8-88 and 18-88 available from Clariant AG Switzerland.
Preferably, the polyvinyl alcohol is present in an amount of about 0.1 to about 5%, such as about 0.5% by weight of the volume of the external aqueous phase;

d) Gelatin, preferably porcine or fish gelatin. Conveniently, the gelatin has a viscosity of about 25 to about 35 cps for a 10% solution at 20 ° C. Typically, a 10% solution has a pH of about 6 to about 7. A suitable trademark is Norland high molecular weight fish gelatin having a high molecular weight, such as obtained from Norland Products Inc, Cranbury New Jersey USA.
Preferably, the gelatin is present in an amount from about 0.01 to about 5%, such as about 0.5% by weight of the volume of the external aqueous phase.

Low viscosity CMC-Na can be conveniently used. Embodiments can be as described above. Typically, low molecular weight CMC-Na is used. The viscosity is from about 1 to about 30 mPa s, for example from about 10 to about 15 mPa s when measured with a Brookfield LVT viscometer with a spindle 1 of 60 rpm in a 1% (w / v) aqueous solution at 25 ° C., or 0.1 to 0.1 mPa s. Viscosity of 1 to 15 mPa * s for a solution of NaCMC 7LF (low molecular weight) as a 1% aqueous solution.
Polyvinyl pyrrolidone having the above properties can be used.

Example 9: Media compositions A to G
The amounts of CMC-Na, mannitol and Pluronic F68 listed in Table 3 are dissolved in about 15 ml hot deionized water at about 90 ° C. with vigorous stirring with a magnetic stir bar. The resulting clear solution is cooled to 20 ° C. and made up to 20.0 ml with deionized water.

Example 12: Release of Compound A from microparticles An amount of microparticles of Examples 2a and 2b corresponding to 4 mg of Compound A / kg of rabbit is suspended in 1 ml of medium composition D. The suspension is homogenized by shaking for about 30 seconds and injected into the left gastrocnemius muscle of a rabbit weighing about 3 kg prior to the start of the test using an 18G needle.
Blood samples (approximately 1 ml) are collected over 55 days. Plasma levels of Compound A are measured using an ELISA method. The average concentration of Compound A after administration is shown in Table 4. Mean AUC (0-55 d) is found to be 296 n g / ml d at 454 n g / ml d and Example 2b Example 2a.

Claims (13)

Embedded in a polymer matrix, Yu releasing, salt form, or protected form cyclo _{[{4- (NH 2 -C 2} H 4 -NH-CO-O-) Pro} -Phg-DTrp-Lys- tyr (4-Bzl) -Phe] wherein, Phg means _{-HN-CH (C 6 H 5} ) -CO-, and Bzl means benzyl. And wherein the polymer matrix comprises linear polylactide-co-glycolide and branched polylactide-co-glycolide . Cyclo _{[{4- (NH 2 -C 2} H 4 -NH-CO-O-) Pro} -Phg-DTrp-Lys-Tyr (4-Bzl) -Phe] is an pamoate salt form, according to claim 1 fine particles according to. 3. Microparticles according to claim 1 or 2, wherein the polymer matrix comprises Resomer (R) RG and a star polylactide-co-glycolide polymer having a weight average molecular weight of 50,000 Da. 4. Microparticle according to any of claims 1 to 3, wherein the ratio of linear polylactide-co-glycolide to branched polylactide-co-glycolide is 50:50. Cyclo [{4- (NH ₂ -C ₂ H ₄ -NH-CO-O-) Pro} -Phg-DTrp-Lys-Tyr (4-Bzl) -Phe] is an amorphous powder having a particle size of less than 5 microns. Fine particles described in 1. Cyclo [{4- (NH ₂ -C ₂ H ₄ 6. The particle size distribution of -NH-CO-O-) Pro} -Phg-DTrp-Lys-Tyr (4-Bzl) -Phe] is x90 <3.0 microns. Fine particles. The fine particles according to any one of claims 1 to 6 , further comprising a surfactant, a porous agent and / or a basic salt . A pharmaceutical composition comprising a water-based medium comprising the microparticles according to any of claims 1 to 7 and a wetting agent. 9. A composition according to claim 8 , wherein the wetting agent comprises a poloxamer and / or a polyoxyethylene-sorbitan-fatty acid ester. 10. A composition according to claim 8 or 9 , wherein the medium comprises an isotonic agent. The composition according to any of claims 8 to 10 , wherein the medium comprises a thickener. A kit comprising the microparticles according to any one of claims 1 to 7 and a water-based medium. 請 Motomeko including a pharmaceutical composition according to any of the microparticles or claim 8, wherein 1 1 of any of 1 to 7, or it contains an excessive over - No GH- and / or IGF-1 secretion A medicament for the treatment of a disease or disorder with an associated etiology.